TWI580421B - Dendrobium polyphenols in the liver, treatment / prevention of diabetes use - Google Patents
Dendrobium polyphenols in the liver, treatment / prevention of diabetes use Download PDFInfo
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- TWI580421B TWI580421B TW102109691A TW102109691A TWI580421B TW I580421 B TWI580421 B TW I580421B TW 102109691 A TW102109691 A TW 102109691A TW 102109691 A TW102109691 A TW 102109691A TW I580421 B TWI580421 B TW I580421B
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/898—Orchidaceae (Orchid family)
- A61K36/8984—Dendrobium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Alternative & Traditional Medicine (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係有關於植物中之活性成份,特別係指一種石斛多酚於保肝、治療/預防糖尿病之用途。
按,近年來由於生活型態之改變,大多數人之飲食習慣由在家用餐變更為至少兩餐皆以外食為主,而長期外食之結果係常會發生蔬菜攝取較少,肉類攝取量偏高等現象,除了會造成攝取營養不均之後果,更因為大多外食食物之油脂、糖份、鹽分含量高,例如:炸雞、含糖飲料等,導致外食者攝取過多熱量,會產生肥胖或是代謝症候群等生理問題。而肥胖對於人類之影響除了外在美觀外,更會使身體內生理作用產生異常,導致非傳染性疾病之罹病率及死亡率之增加,損害生活品質,例如:造成肝臟累積過多脂肪,使得肝臟無法發揮正常之脂肪代謝功能,無法處理過剩之脂肪,因而造成脂肪肝;亦或胰島素之分泌不正常,造成體內脂肪代謝異常,因而直接或是間接地導致如二型糖尿病之疾病產生。
更進一步而言,所謂脂肪肝,乃係指肝內脂肪佔肝臟重量超過10%者。輕度脂肪肝雖對於人體無立即性之重大危害,惟,長期性脂肪浸潤肝臟,將使肝細胞慢性發炎,而提高肝臟病變之風險,如肝硬化、肝癌等;此外,脂肪肝患者之肝臟合成高密度脂蛋白減少,低密度脂蛋白及極低密度脂蛋白增加,而得引起高血脂症,並增加罹患中風或心臟病之可能性。而糖尿病乃係目前常見慢性病之一,大多數患者初期認為其症狀不明顯而忽略治療,然長期觀之,糖尿病係會引發許多慢性併發症,如腎臟病變、視網膜病變,亦為動脈硬化之危險因子,會加速心血管疾病之發生。
再者,據統計大約半數之脂肪肝患者係合併有糖尿病,而約半數糖尿病患者係患有脂肪肝,其主因乃在於肥胖之糖尿病患者大多存在高胰島素血症及胰島素抗性,而誘使肝臟三酸甘油酯合成增加,並堆積於肝臟。目前臨床上並無能完全治癒該二種疾病之藥物,僅能針對病徵而投予適當藥物,配合改變生活習慣,減緩症狀及控制病情。
為了改善西藥所產生之副作用,以及民眾對於日常保健觀念之提昇,因此,目前許多相關研究係以中草藥為研究對象,例如:石斛(Dendrobium species)。詳言之,石斛為一種生長於熱帶及亞熱帶地區之蘭科植物,多用於觀賞之切花(out flowers)及盆花(potted orchids)。石斛屬(Dendrobium genus)植物包含約1600種,其中15種係在台灣被發現。而於中醫治療應用上,經乾燥之石斛或是新鮮之石斛莖部係為一種名貴之中草藥(Dendrobium spp.;Herba Dendrobii),得用以退燒、眼科或是滋補身體。近期之研究中更指出石斛內含有許多活性物質,如菲基(phenanthrenes)、雙苄(bibenzyls)、茐酮(fluorenones)和倍半萜(sesquiterpenes)、生物鹼(alkaloids)而得分別具有不同活性,如消炎(anti-flammatory)、抗氧化劑(antioxidant)或抗過敏(antiallergic)等。
由此可知石斛屬植物確為一種珍貴且對於人體健康有助益之植物,惟,過去研究係未將石斛屬植物用於肝臟疾病或是糖尿病,因此,本案發明人乃致力研究石斛屬植物之活性成份,希冀其能用於改善糖尿病或是肝臟疾病。
本發明之主要目的即在於提供一種使用石斛多酚於製造治療肝臟疾病之醫藥組合物之用途,其中:該石斛多酚係萃取自石斛屬植物之非多醣混合物,如黃花石斛植物,而至少包含一石斛酚,如下式(I)所示:
該肝臟疾病係得為脂肪肝、肝硬化、肝纖維化或肝炎。
本發明之另一目的係在於提供一種使用石斛多酚於製造治療糖尿病之醫藥組合物之用途,其中:該石斛多酚係萃取自石斛屬植物非多醣混合物,如黃花石斛植物,而至少包含一石斛酚,如上式(I)所示。
本發明之次一目的係在提供一種石斛多酚作為食品之用途,其中:該石斛多酚係萃取自一石斛屬植物之非多醣混合物,如黃花石斛植物,而至少包含一石斛酚,如上式(I)所示。
該食品係為保肝食品或是用以調控血糖之食品。
第一圖係為石斛多酚以高效能液相層析儀分析所得之圖譜。
第二圖係為石斛酚標準品以高效能液相層析儀分析所得之圖譜。
第三圖係為石斛酚標準品以高效能液相層析儀測量所得之線性回歸檢量線。
第四圖係為測量各組小鼠體重之結果。
第五圖係為測量各組小鼠血清中轉氨酶含量之結果。
第六圖係為測量各組小鼠肝臟中三酸甘油酯含量之結果。
第七圖係為各組小鼠肝臟組織切片以蘇木紫/伊紅染色之結
果,其中,A為第一組,B為第二組,C為第三組,D為第四組。
第八圖係為各組小鼠經口服葡萄糖耐受性試驗後於不同時間所測得之血糖值。
第九圖係為測量各組小鼠血清中轉氨酶含量之結果。
第十圖係為測量各組小鼠肝臟中IL-6之結果。
第十一圖係為測量各組小鼠肝臟中羥脯氨酸之結果。
第十二圖係為各組小鼠肝臟組織切片以蘇木紫/伊紅染色之結果,其中,A為第一組,B為第二組,C為第三組,D為第四組。
第十三圖係為各組小鼠肝臟組織切片以膠原蛋白專一性染劑染色之結果,其中,A為第一組,B為第二組,C為第三組,D為第四組。
以下,將茲舉本發明若干實例並配合圖式作更進一步說明如后。
本發明所揭之石斛多酚係由一石斛屬植物所萃取之非多醣混合物,由於石斛屬植物種類眾多,因而在以下之實例中將僅以黃花石斛為例,特此敘明。
取一黃花石斛莖部,以常溫乾燥後研磨成粉,而稱取約30克之粉末溶於300毫升之甲醇(methanol)中,並以超音波震盪器震盪10分鐘,而獲得一石斛/甲醇萃取物。將該石斛/甲醇萃取物依序以正己烷(n-hexane)萃取三次,再以乙酸乙酯(ethyl acetate,EA)萃取三次,去除濾液而得到一石斛多酚。
更進一步者,將該石斛多酚以高效能液相層析儀(High
performance liquid chromatography)以一預定條件下進行分析,結果如第一圖所示。
取一石斛酚標準品,其結構式如下所示:
將該石斛酚標準品以高效能液相層析儀以一預定條件下進行分析,結果如第二圖所示。再將該石斛酚標準品製備為濃度分別為6.25mg/L、12.5 mg/L、25 mg/L、50 mg/L、100 mg/L、200 mg/L,而經高效能液相層析儀測量,製作而得一線性回歸檢量線,公式為Y=32.363X-1.003(R2=0.9999),如第三圖所示。
由第二圖可知石斛酚於管柱內之滯留時間約為22分鐘處,而比對第一圖及第二圖之結果,可知該第一圖可知於滯留時間約為22分鐘處係具有一明顯波峰,顯示本發明所揭之石斛多酚之成份中至少包含有石斛酚。
更進一步者,係將該石斛多酚中對應該石斛酚標準品之積分面積帶入該線性回歸檢量線之公式,而測得該石斛多酚中所含有之石斛酚量為100.26±1.85 μg/g。
取複數隻C57BL/6小鼠而分為四組,各該組小鼠係先經一週適應環境後而分別以不同條件飼養八週,其中,第一組係為正常小鼠;第二組係為餵食濃度30%之果糖水,以誘發脂肪肝發生;第三組係同時
餵食濃度30%之糖水及本發明所揭之石斛多酚,劑量為10mg/kg;第四組係同時餵食濃度30%之糖水及本發明所揭之石斛多酚,劑量為50mg/kg。
分別測量實例三中各該組小鼠之體重,結果如第四圖所示,可知第二組小鼠之體重顯著高於第一組小鼠,顯示餵食高濃度果糖水確實會造成體重增加,而得誘導形成脂肪肝模式小鼠;而相較於第二組小鼠,第三組及第四組之體重係分別有顯著降低,顯示餵食高劑量或低劑量之石斛多酚係具有體重降低之功效。
轉氨酶(Alanine Aminotransferase;ALT)係為肝臟內之一種酵素,一般用以作為檢測肝功能之指標,當血清中之血清轉氨酶含量高於正常值時,表示肝臟有損傷或是發炎之現象產生。
因此,於本實例中係分別檢測實例三中各該組小鼠血清中轉氨酶之含量,結果如第五圖所示,可知第二組小鼠血清中轉氨酶之含量係顯著高於第一組小鼠者,顯示餵食高濃度糖水確實會造成血清中轉氨酶之含量,推知高濃度果糖水應會造成肝損傷;而相較於第二組小鼠,第三組及第四組小鼠血清中之轉氨酶含量分別有顯著降低,顯示餵食高劑量或低劑量之石斛多酚係皆具有降低血清中轉氨酶含量之功效。
於本實例中係分別檢測實例三中各該組小鼠肝臟中三酸甘油酯之含量,結果如第六圖所示,可知第二組小鼠肝臟中三酸甘油酯之含量顯著高於第一組,顯示餵食高濃度果糖水係會造成肝臟中三酸甘油酯增加,而形成脂肪肝;而比對第二組之結果,第三組與第四組之小鼠肝臟中三酸甘油酯含量係分別具顯著降低,顯示餵食本發明所揭石斛多酚,不論高劑量或低劑量,係分別皆可有效降低肝臟中三酸甘油酯之含量,而抑制脂肪肝形成。
更進一步,將各該組小鼠之肝臟組織分別以福馬林固定,再以石蠟包埋切片後,以蘇木紫/伊紅染色,經脫水封片後,於光學顯微鏡下觀察拍照,結果如第七圖所示,其中,第七圖A係為第一組;第七圖B係為第二組;第七圖C係為第三組;第七圖D係為第四組。
由第七圖之結果可知由於第二組小鼠係為高果糖所誘導之脂肪肝模式小鼠,肝臟內脂肪組織較多,肝臟內脂肪空泡明顯;而相較於第二組,第三組或第四組之脂肪組織形成較少,脂肪組織空泡亦較不明顯,顯示餵食本發明所揭之石斛多酚係具有抑制脂肪肝形成之作用。
必須先加以說明者,胰島素阻抗性係指特定胰島素濃度所引起之降血糖反應不如正常狀態,而造成血液中糖份含量偏高。胰島素阻抗係為造成第二型糖尿病之基本病因,大多數第二型糖尿病病患係有胰島素阻抗性。
於本實例中係先分別測量實例三之各該組小鼠於空副食之血糖值,而後口服給予各該組小鼠劑量為2.0(g/kg)之葡萄糖,再分別測量各該組小鼠於餵食後30、60、90及120分鐘之血糖值,結果如第八圖所示。並進一步藉由各該組小鼠口服葡萄糖耐受性試驗評估其胰島素阻抗性。而由第八圖之結果可知第二組小鼠之血糖升高,而與第一組具有顯著差異,並推得第二組小鼠具胰島素阻抗性;第三組及第四組之小屬於口服葡萄糖後能分別於30、60、120分鐘使血糖降低,而與第二組間具有顯著差異,亦即第三組及第四組小鼠係不具有胰島素阻抗性,顯示本發明所揭之石斛多酚,於高劑量或是低劑量下,皆能減少胰島素阻抗之情形發生,並有效地調控血糖。
取複數隻ICR小鼠而分為四組,各該組小鼠係先經一週適應環境後,再分別以不同條件處理而飼養八週,其中,第一組係未經任何
處理,為正常小鼠;第二組係以硫代乙醯胺(thioacetamide,TAA)200mg/kg進行腹腔注射,用以誘發肝炎;第三組係以硫代乙醯胺200mg/kg進行腹腔注射,並同時投予本發明所揭之石斛多酚,劑量為10mg/kg;第四組係以硫代乙醯胺200mg/kg進行腹腔注射,並同時投予本發明所揭之石斛多酚,劑量為50mg/kg。
檢測實例八中之各該組小鼠血清中轉氨酶之含量及肝中IL-6之含量,結果如第九圖及第十圖所示,其中,第九圖係為各該組小鼠血清中轉氨酶含量;第十圖係為各該組小鼠肝中IL-6之含量。
由第九圖之結果可知第二組之轉氨酶含量係顯著高於第一組,顯示投予硫代乙醯胺確實會造成轉氨酶增加;第三組或第四組與第二組相比,其轉氨酶含量係顯著降低。
由第十圖之結果可知第二組之IL-6係顯著高於第一組,顯示第二組小鼠係具有肝發炎之現象;而與第二組相比,第三組或第四組之IL-6量皆顯著降低。
由上結果顯示注射硫代乙醯胺係會誘導小鼠產生肝炎,造成血清中轉氨酶含量增加,而餵食本發明所揭之石斛多酚,無論為高劑量或是低劑量,皆會抑制肝炎之發生。
由於肝臟內羥脯氨酸(hydroxyproline)含量係為肝臟纖維化之重要指標,因此,於本實例中係檢測實例八中之各該組小鼠肝內羥脯氨酸含量,並更進一步將各該組小鼠之肝臟分別進行組織切片,並分別以蘇木紫/伊紅以及膠原蛋白專一性染劑(sirius red)進行染色,結果如第十一圖至第十三圖所示,其中,第十一圖係為各該組小鼠肝內羥脯氨酸之含量;第十二圖係為各該組小鼠肝臟組織切片以蘇木紫/伊紅染色之結果;第十三圖係為各該組小鼠肝臟組織切片以膠原蛋白專一性染劑染色之結
果;而第十二圖A及第十三圖A係為第一組;第十二圖B及第十三圖B係為第二組;第十二圖C及第十三圖C係為第三組;第十二圖D及第十三圖D係為第四組。
由第十一圖結果可知第二組肝中羥脯氨酸係顯著高於第一組,顯示投予硫代乙醯胺係會造成肝中羥脯氨酸含量增加;而第三組及第四組肝中羥脯氨酸含量係分別顯著低於第二組者。
由第十二圖及第十三圖之結果可知第二組肝臟組織內脂肪空泡係較明顯,並纖維化組織之沈積係較多,而另觀第三組及第四組之肝臟組織內脂肪空泡係較不明顯,且纖維化組織之沈積亦較少。
由上述結果顯示餵食本發明所揭之石斛多酚者,不論為低劑量或高劑量,係分別可以降低肝纖維化之形成以及抑制脂肪肝之形成。
藉由各該實例之說明,本發明所揭之石斛多酚係為萃取自藥用植物中之活性成份,具有對抗如肝臟纖維化、肝臟脂肪堆積、肝臟發炎等肝臟病變、調控血糖以及降低體重之功效,得用以製造作為治療肝臟疾病或是糖尿病之醫藥組合物,或是作為一食品,用以保肝或是調控血糖。
其中,此所謂之該醫藥組合物係將本發明所揭之石斛多酚搭配一醫藥上可接受之載體及/或賦形劑製造而成者,得為任何型態,如丸型、錠劑、粉狀、液態、膠狀、噴霧等,亦得以任何方式投予,如口服、注射等,皆可達成本發明之功效。
再者,本創作所揭之該石斛多酚,係得搭載任何一食物組成份而成為一食品,該食品得為飲品、口嚼錠、餅乾、糖果或以任何形式供食用之產品,亦可達成本發明之功效。
此外,本發明所揭之該石斛多酚除如上開實例中得以甲醇及乙酸乙酯為溶劑萃取而得外,亦得以酒精、水或一般得於萃取方法中所使用之溶劑作為萃取溶劑。
上述說明係針對本發明之可行實施例之具體說明,為該實施
例並非用以限制本發明之專利範圍,凡未脫離本發明技術特徵所為之等效實施或是變更,均應包含於本案之專利範圍中。
Claims (5)
- 一種使用石斛多酚於製造治療肥胖之醫藥組合物之用途,其中,該石斛多酚係以下列方法所製備而成者:步驟A:取一石斛屬植物粉末,溶於一第一溶劑中,形成一石斛溶液,而該第一溶劑係選自由甲醇、乙醇、水及乙酸乙酯所組成之群;步驟B:以超音波震盪法自該石斛溶液萃取出一石斛萃取物;步驟C:以選自由水、乙醇、乙酸乙酯及甲醇所組成之群之一溶劑自該石斛萃取物萃得該石斛多酚。
- 依據申請專利範圍第1項所述用途,其中,該石斛多酚係至少包含一石斛酚,如下式(I)所示:
- 依據申請專利範圍第1項所述用途,其中,該石斛屬植物係為黃花石斛。
- 一種石斛多酚於製造治療肥胖之組合物之用途,其中,該石斛多酚係以下列方法所製備而成者:步驟A:取一石斛屬植物粉末,溶於一第一溶劑中,形成一石斛溶液,而該第一溶劑係選自由甲醇、乙醇、水及乙酸乙酯所組成之群;步驟B:以超音波震盪法自該石斛溶液萃取出一石斛萃取物;步驟C:以選自由水、乙醇、乙酸乙酯及甲醇所組成之群之一溶劑自該石斛萃取物萃得該石斛多酚。
- 依據申請專利範圍第4項所述用途,其中,該石斛多酚係至少包含一石斛酚,如下式(I)所示:
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CN104887957A (zh) * | 2015-06-11 | 2015-09-09 | 孙太辉 | 一种治疗糖尿病及高血糖的药物及其制备方法 |
CN105147993A (zh) * | 2015-08-20 | 2015-12-16 | 金思思 | 一种治疗老年性糖尿病的药剂 |
CN105267633A (zh) * | 2015-10-26 | 2016-01-27 | 鲁洪艺 | 治疗高血糖、糖尿病的中成药 |
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